Background: Napsin-A is an aspartic protease that is predominantly expressed in the proximal renal tubules and type II pneumocytes. Although it has been reported to be present in a proportion of renal cell carcinomas (RCCs), utilization of napsin-A immunohistochemistry as a routine diagnostic tool for RCC, and the correlation of the level of expression with histological features and clinical outcomes have not yet been established.Design: Using tissue miscoarrays we assessed the immunohistochemical expression of napsin-A in a cohort of clear cell and papillary RCCs including 81 and 125 primary and metastatic cases, respectively, in addition to 24 primary and matched metastatic cases.Results: Napsin-A expression was demonstrated in 86 of 222 (39%) clear cell RCCs (CRCCs) and 16 of 21 (76%) papillary RCCs (PRCCs) with a strong and diffuse staining pattern observed in PRCC and a relatively weak and focal positivity in CRCCs. Compared with primary CRCCs, a comparable proportion of metastatic CRCCs retained napsin-A expression (45/132, 34%), suggesting the potential utility of napsin-A in the evaluation of metastatic tumors. The expression of napsin-A was also found to be inversely correlated with aggressive local tumor characteristics, such as advanced pathological stage (27/49 for T1/T2 vs 12/41 for T3/T4) and high Fuhrman nuclear grade (33/60 for grades 1/2 vs 8/30 for grades 3/4). Lastly, the expression of the marker correlated inversely with survival in a cohort of 22 patients with locally advanced CRCCs and an overall follow-time of 45 months; while none of patients who died of RCC (0/10) expressed napsin-A in their primary tumors, half (4/8) of those showing no evidence of disease post-nephrectomy expressed the marker. Patients alive with disease were intermediate between the two groups (25%) (p = 0.04).Conclusions: Our findings show the utility of napsin-A in the diagnosis of CRCC but especially PRCC. Napsin-A can therefore be added to the list of markers routinely used in the diagnosis of PRCC as it stains the majority of our cases in a strong and diffuse fashion. It can also be valuable in the diagnosis of metastatic PRCC and CRCC. In the current study, napsin-A expression was inversely related to adverse clinical outcome and aggressive local tumor characteristics such as advanced pathological stage and high nuclear grade.Category: Genitourinary (including renal tumors)